tbuckley/cabot-search huggingface dataset:
Characteristics of CRC01, an investigational CD19 CAR-T product with PD-1 and TIGIT genes silenced by shRNAs.
Authors: YoungSam Park, Dong-Hyuk Jeon, Hyunhwan Yi, Sang-Hoon Lee, Hyung Cheol Kim
Journal: Journal of Clinical Oncology (2022)

e14514 Background: Currently, CAR-T therapy has been successful in the treatment of certain types of hematological malignancy. However, not all patients benefit from this novel therapy due to various resistance mechanisms, such as suppression of immune cell function by inhibitory immune checkpoint signaling. To overcome this, we have developed a novel two-in-one lentiviral vector system that can efficiently induce shRNA-based silencing of PD-1 and TIGIT genes in CAR-T cells while maintaining robust CAR expression. This PD-1 and TIGIT-silenced CD19 CAR-T, CRC01, showed an enhanced anti-tumor activity in vitro and in vivo, compared to conventional CD19 CAR-T. For the development of CRC01 as an investigational new drug, IND-enabling non-clinical studies have been conducted and CRC01 is currently being evaluated in a clinical trial for r/r LBCL patients (NCT04836507). Methods: T cells were enriched from leukapheresis products of r/r LBCL patients and transduced with the two-in-one lentiviral vector. Transduced T cells were expanded within a semi-closed culture system and formulated for cryopreservation. For phase I clinical trial of CRC01, ten batches of CRC01 were manufactured and characterized in quality. Results: In the manufacturing of ten batches of CRC01, manufacturing time was in the range of 8-14 days and total cells expanded 32-53 folds. In the final product of CRC01, T cell percentage (Live CD3+) and viability were not less than 98% and 85%, respectively. The range of transduction efficiency was 11.3%-28.6% and the range of vector copy number was 1.0-3.5 copies/CAR-T. Generally, CRC01(CAR-positive T cells) showed higher CD4/CD8 ratio than leukapheresis product and CAR-negative T cells, and central memory and effector memory T cell subsets were the main populations of CRC01. All batches of CRC01 released IFN-γ in response to CD19-expressing target cells, but the level of IFN-γ production was quite different from batch to batch. When PD-1 and TIGIT expression levels of CRC01 were analyzed after CD3/CD28 stimulation, CAR-positive T cells were found to express PD-1 and TIGIT much lower than CAR-negative T cells, demonstrating an efficient silencing of PD-1 and TIGIT genes in CRC01. Conclusions: Ten batches of CRC01 were manufactured in GMP facility for CRC01 phase I clinical trial. All batches met acceptance criteria for release, showing that CRC01 manufacturing process is a robust one and that silencing of PD-1 and TIGIT genes via shRNAs, a unique feature of CRC01, was successfully implemented in the investigational products.
Cardiomyocytes (CM) derived small Extracellular Vesicles (sEV) plays an important role in heart development
Authors: C Balbi, D Ceresa, C Schiano, P Malatesta, L Barile, G Vassalli
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Schweizerische Herzstiftung - FF21017 Fondazione Leonardo Introduction Neonatal rats have the capacity to regenerate their hearts in response to injury, but this potential is lost after the first week of life. Cardiac maturation lays the foundation for postnatal heart development and disease, yet little is known about the contributions of the microenvironment to cardiomyocyte maturation. Extracellular vesicles (EV) are bilayer-membrane nanoparticles released by all cell types, carrying proteins, lipids, and nucleic acids, which reflect the activation state of parental cells. Secreted small extracellular vesicles (sEV), prominently figure among extracellular signals that regulate cell function. Purpose We aim to determine whether cardiomyocyte (CM) derived sEV carried miRNA that has a role in heart development with specific regards to cardiomyocyte maturation. Methods sEV were isolated from rat cardiomyocyte at day 0 and 7 after birth by serial ultracentrifugation. sEV were characterized by NTA and analyzed by Western blot for the presence of classical EV markers (TSG101, Syntenin-1). The role of sEV in cardiomyocyte proliferation was assesed by analysis of EdU incorporation on neoantal rat CM treated with sEV_p0 or sEV_p7. miRNA content on sEV was assesed using a rat-miRNome MicroRNA Profiling Kit and the identified miRNA's targets confirmed by RealTime-PCR and Western Blot. Results NTA and Western Blot analysis confirmed the presence of sEV in both the extracellular vesicles preparation. sEV_p0 showed to be able to sligtly increase EdU incorporation in treated cardiomyocyte (1.15-Fold) while sEV_p7 significantly inihibit CM proliferation (0.78-Fold) toghether with a change in cardiomyocyte citoscheletal architecture. Data from miRNome analysis showed in sEV_p7 a significan increase in miRNA with cyclines as tagets. Downregulation of Cdk1 ; Cdk4 ; Cdk2 ; CcnB1 and CcnD1 was confirmed on CM trated with sEV_p7 compared to Ctrl. Downregulation of CCND1 was aslo confrmed at the protein level by Western Blot analysis. Conclusions These preliminary resultes showed an important role in heart develompent of cardiomyocyte derived-sEV. A deeper investigation of the pathaway activated by sEV may have a potential interest for the identification of possible regulators for stimulating heart regeneration.
Racial and ethnic disparities in adherence and reported symptoms during routine collection of patient-reported outcomes (PROs).
Authors: Samuel U Takvorian, Yaxin Wu, Peter Edward Gabriel, Michelle Iocolano, Justin E. Bekelman, Lawrence N. Shulman, Ravi Bharat Parikh
Journal: Journal of Clinical Oncology (2022)

6510 Background: Routine collection of PROs for patients with cancer is an evidence-based practice and critical component of high-quality cancer care, but real-world adherence and reporting patterns are poorly understood. We examined differences in PRO adherence and reported symptoms by race and ethnicity. Methods: We conducted a retrospective cross-sectional study using de-identified electronic health record data from a National Cancer Institute Comprehensive Cancer Center. Participants included adults seen in follow-up at one of two medical oncology practices (1 academic, 1 community) from June 2019 to February 2020, during which two validated PRO instruments (NCI PRO-CTCAE and PROMIS Global v1.2) were routinely administered electronically via portal or tablet at return visits. Adherence was defined for each participant as the proportion of visits in which a PRO questionnaire was completed within 30 days. Using ordinary least squares regression, we modeled patient adherence as a function of race/ethnicity and adjusted for age, sex, insurance, median area income, ECOG performance status, cancer type, cancer stage, visit site, and number of visits during the study. Among study participants completing at least one PRO questionnaire, we modeled reported symptoms from the first questionnaire using a similar approach. Results: From June 2019 to February 2020, there were 29,726 patients (mean [SD] age 60.8 [15.1] years; 18,045 [60.7%] female) seen across 111,262 medical oncology visits. Of these patients, 19,971 (67.2%) completed at least one PRO questionnaire. Adjusted mean PRO adherence and reported symptoms varied by race/ethnicity, with Black and Hispanic patients reporting significantly higher symptom burden than White patients (Table). Conclusions: In this large cohort reflecting real-world PRO collection patterns, Black and Hispanic patients were less likely than White patients to complete PRO questionnaires, but more likely to report more severe symptoms. There is urgent need to ensure equitable PRO access and implementation and to address greater reported symptom burden among minority patients. [Table: see text]
RONC-17. Feasibility of proton therapy with and without simultaneous chemotherapy in CNS malignancies of children and adolescents
Authors: Eicke Schuermann, Stephan Tippelt, Julia Zeller, Dirk Geismar, Danny Jazmati, Sarah Peters, Beate Timmermann, Ruth Mikasch, Gudrun Fleischhack
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: Proton therapy (PT) is a valuable alternative to photon radiotherapy in treatment of CNS tumors in children and adolescents. The aim of this study was to investigate the feasibility of recent treatment strategies with a particular focus on the acute toxicity of a simultaneous radiotherapy and chemotherapy (sRCT). PATIENTS AND METHODS: We investigated 199 patients (116 male, 83 female, median age 7.4 years) who received in total 200 cycles of PT (60.5% at new diagnosis, 39.5% at relapse) from September 2013 to February 2017. Entities included ependymomas (34%), medulloblastomas (16%), low grade gliomas (13%), ATRTs (12%), craniopharyngiomas (9%), germ cell tumors (6%), and other entities (10%). SRCT was administered in 52 (26%) treatment cycles. The target tumor was predominantly localized infratentorial (53%), supratentorial (23.5%) and supra-/intrasellar (18%). 38 patients received additional CSI and 8 patients a boost to metastases. Data were collected retrospectively based on patient records. Toxicity was documented according to CTCAE version 4.03. RESULTS: Severe adverse events (SAE ≥ grade 3) occurred in 33.5% of all patients, in particular in form of hematotoxicity (64.1%) and infections (26.8%). In-patient treatment for unexpected SAEs was necessary in 33 patients (16.5%). In the group treated with sRCT 15 out of 52 (28.8%) patients couldn’t receive the recommended dose or time schedule of planned chemotherapy due to SAEs. Comparing the SAE frequency in both groups, the children who have been treated with sRCT had a significantly higher risk of SAEs than the patients who have received proton therapy only (63.5% vs. 23.0%, p=0.001). CONCLUSIONS: PT and concomitant chemotherapy are feasible, but require an interdisciplinary team with continuous out-/inpatient management of patients, as the risk of toxicity is significantly increased. Risk-adapted adjustment of simultaneous chemotherapy is necessary to reduce relevant interruptions of radiotherapy. Funded by the German Childhood Cancer Foundation
Monitoring engorgement of phagocytic circulating stromal cells during chemo-radiotherapy induction predicts survival in unresectable stage 2/3 NSCLC.
Authors: Kirby P Gardner, Daniel L Adams, Pablo Lopez Bravo, Jianzhong He, Yawei Qiao, Ting Xu, Zhongxing X. Liao, Cha-Mei Tang, Steven H. Lin
Journal: Journal of Clinical Oncology (2022)

3054 Background: Circulating stromal cells, ie Cancer Associated Macrophage-Like cells (CAMLs), are prevalent in the circulation of non-small cell lung carcinoma (NSCLC) patients (pts), appearing as giant phagocytic macrophages that represent an inflammatory pro-tumorigenic microenvironment. Previously it was shown that pts with engorged CAMLs of ≥50µm after treatment are prognostic for poor clinical outcomes. However, analyzing the dynamic changes in CAMLs over time or in response to treatment, ie chemoradiation (CRT) and immunotherapy (IMT) has not been evaluated. We monitored n = 182 unresectable NSCLC stage II/III pts treated with CRT alone (n = 91) or with concurrent IMT (n = 91) to evaluate changes in CAMLs before and after CRT induction at it relates to progression free survival (PFS) or overall survival (OS). Methods: We prospectively procured pts from 3 different regimes, treated with CRT alone (n = 91), treated concurrently with CRT &amp; Atezolizumab (n = 40, clinical trial NCT02525757), or treated concurrently with Durvalumab (n = 51). We recruited 182 pts with pathologically confirmed stage II/III unresectable NSCLC. A total of 15 mL blood samples were drawn prior to start of therapy at baseline (BL) and ̃5 weeks (T1) after CRT induction. Blood filtration was done using CellSieve filters, then CAMLs were identified and measured to evaluate PFS &amp; OS hazard ratios (HRs) by censored univariate and multivariate analyses at 2 years. Results: CAMLs were found in 89% of all samples tested. Increases in CAML size between BL &amp; T1 were significantly correlated with worse clinical outcomes, with higher CAML increases correlated with increasingly worse outcomes, including CAML increases &gt;10μm resulting in PFS HR=1.7 p = 0.027 &amp; OS HR=1.9 p = 0.045, through increases &gt;40μm resulting in PFS HR=2.1 p = 0.013 &amp; OS HR=2.5 p = 0.020. Increases of CAMLs &gt;35μm was optimal at stratifying pts PFS HR=2.2 p = 0.005 &amp; OS HR=2.8 p = 0.005. Specifically, pts treated with only CRT and increasing CAMLs &gt;35μmhad significantly worse PFS HR=2.7 p = 0.029 &amp; OS HR=4.1 p = 0.013. In parallel, pts treated with CRT+IMT and increasing CAMLs &gt;35μm had near significance for worse PFS (HR=2.1 p = 0.073) &amp; OS (HR=2.3, p = 0.147), though follow up clinical data is ongoing. Conclusions: Our data suggest that in unresectable stage II/III NSCLC, tracking the increase of pro inflammatory immune cells (CAMLs) in circulation during therapy induction can identify pts less responsive to CRT or PD-L1/PD-1 IMTs.
3D-volumetric assessment of response to ivosidenib in IDH-mutant gliomas.
Authors: Sushant Puri, Jessica Shi, Lindsay Blair, Jaishri O'Neill Blakeley, John Laterra, David Kamson
Journal: Journal of Clinical Oncology (2022)

2063 Background: Isocitrate Dehydrogenase (IDH) mutant gliomas represent a distinct class of primary brain tumors. Mutant IDH is a driver mutation implicated in gliomagenesis and a potential therapeutic target. Ivosidenib, an inhibitor of mutant IDH1, is currently being evaluated to treat gliomas. In the present study we assess our single-institutional experience with the off-label use of ivosidenib to reduce tumor growth rate in patients with IDH mutant gliomas. Methods: We have longitudinally analyzed the imaging of patients with histology-proven radio- and chemotherapy-naïve IDH-mutant WHO Grade 2 and 3 astrocytomas (AS) and oligodendrogliomas (OG) treated with off-label ivosidenib between 2019 and 2022. First, each patients’ FLAIR images were anonymized, bias-corrected, co-registered and semi-automatically segmented for volumetric analysis using 3D Slicer 4.11. MR acquisition dates were hidden, and the order of scans was randomized to prevent expectation bias. Volumetric trends and PFS were analyzed. Progressive disease was defined as a ≥40% increase in volume from baseline as per modified RANO criteria. Results: Eleven patients were included in the analysis (median age 46 years [range 26-62], 2F, 8AS/3OG, 7 Grade 2). Mean±SD follow-up time on ivosidenib was 16.1±15.5 months. Tumor volume reduction was noted in 82% of patients at least at one time point. Average volume change at best response was -11.4±12.8%. Mean time to best response was 12.1±9.3 months. PFS-6 and PFS-12 were 91% (n = 11), and 88% (n = 8), respectively. Mean PFS was 24.4 months (CI95% 18.8-29.9). Median PFS was not reached. Patients older than 45 years had significantly higher volume reduction compared to younger patients (18.9±6.3% vs. -2.4±13.2%;-p = 0.047, 2-tailed T-test). Ivosidenib was discontinued in in 2 patients for 2D radiographic changes, and in one for increased seizure frequency. Conclusions: The use of ivosidenib in treatment-naïve gliomas was associated with a high response rate; however, on average it required longer than a year to achieve best response. In this cohort, older patients had higher volume reduction. The drug was well tolerable. Further analysis of an expanded cohort is underway.
ATRT-10. Single-cell transcriptional profiling of ATRTs reveals heterogeneous signatures of tumor and non-malignant cell populations
Authors: Enrique Blanco-Carmona, Annette Büllesbach, Aniello Federico, Ilon Liu, Matthew D Young, Gerda Kildisuite, Sam Behjati, Rajeev Vibhakar, Andrew Donson, Nicholas Foreman, Volker Hovestadt, McKenzie Shaw, Susan Chi, Michael Frühwald, Jarno Drost, Andrey Korshunov, Martin Hasselblatt, Stefan M Pfister, Natalie Jäger, Pascal Johann, Mariella Filbin, Marcel Kool
Journal: Neuro-Oncology (2022)

Abstract Atypical Teratoid/Rhabdoid Tumors (ATRTs) are known for exhibiting high inter-tumor heterogeneity, even though they are almost all characterized by a common loss of SMARCB1 (or rarely SMARCA4). Three subgroups have been identified at bulk methylome and transcriptome level: ATRT-TYR, ATRT-SHH, and ATRT-MYC. To better understand the biology underlying each subgroup and potentially unveil their (different) cell(s) of origin, we performed single-cell transcriptomic analyses in 22 ATRTs using fresh frozen samples and both 10X and Smartseq technology. All data, grouped by technology, underwent quality control and normalization, regressing out the biases introduced by each sample. Tumor microenvironment (TME) and tumor bulk (TB) clusters were characterized by a combination of copy number variant analyses, enrichment in literature lists of marker genes for specific cell populations, and in-depth analysis of differentially enriched (DE) genes. Non-negative Matrix Factorization (NMF) was applied to TB to reveal major transcriptional profiles, which were grouped into meta-signatures. A total of 71 gene lists were retrieved from NMF (TB) and DE analyses (TME + TB), that gathered into 11 signature groups by Jaccard similarity, with one extra group accounting for unique signatures. Three groups targeted TME, accounting for either microglia, fibroblasts and endothelial cells, or OPCs, oligodendrocytes, astrocytes and neurons. These signatures are enriched in specific clusters across technologies. The remaining eight groups divide into two types, either enriched in clusters predominantly formed by cells of one or two ATRT subgroups or signatures enriched for a particular phenotype, such as cilial, cycling, axonogenesis or EM transition. While the first type is enriched across clusters in a gradient fashion, the second shows enrichment for selected clusters across technologies. Further analyses on the integrated dataset and additional samples are ongoing to validate and refine these 11 signature groups in ATRTs to see how this may lead to new treatment approaches.
A Dual‐Bioinspired Tissue Adhesive Based on Peptide Dendrimer with Fast and Strong Wet Adhesion
Authors: Haofang Zhu, Guoming Xu, Yiyan He, Hongli Mao, Deling Kong, Kui Luo, Wenbo Tang, Rong Liu, Zhongwei Gu
Journal: Advanced Healthcare Materials (2022)

Abstract Although tissue adhesives have potential advantages over traditional sutures, existing ones suffer from several limitations: slow adhesion kinetic, low mechanical strength, and poor interfacial bonding with wet biological tissues. Herein, a cooperative mussel/slug double‐bioinspired hydrogel adhesive (DBHA) composed of a robust adhesive interface and a stretchable dissipative matrix is developed. The DBHA is formed by a cationic polysaccharide (chitosan), an anionic polysaccharide (carboxymethyl cellulose), and a barbell‐like dendritic lysine grafted with catechol groups (G3KPCA). Compared to various commercial bio‐glues and traditional adhesives, the DBHA has significantly stronger tissue adhesion and enhanced toughness both ex vivo and in vivo. Meanwhile, the DBHA exhibits fast, strong, tough, and durable adhesion to diverse ex vivo tissue surfaces with blood. The adhesion energy between the adhesive and porcine skin can reach 200–900 J m −2 . Additionally, in vivo studies prove that DBHA has good hemostasis of rabbit artery trauma and achieves better wound healing of tissue incision than commercial bio‐glues. This study provides a novel strategy for fabricating fast and strong wet adhesives, which can be used in many applications, such as soft robots, tissue adhesives and hemostats.
Pediatric Cancer Registry in Turkey 2009-2021 (TPOG &amp; TPHD).
Authors: M. Tezer Kutluk, Akif Yeşilipek
Journal: Journal of Clinical Oncology (2022)

e22020 Background: The pediatric cancers is in the global agenda to improve the survival rates which is still low in LMICs although it is more than 80% in HICs. More than 300.000 pediatric cancer cases annually are expected in children and adolescents aged 0-14 globally. Registry is the first step of an efficient cancer control. Here, we present the most updated results of the pediatric cancer registry fromTurkey. Methods: Turkish Pediatric Oncology Group and Turkish Pediatric Hematology Association has established the pediatric cancer registry in 2002. The childhood cancer cases registered between 2009-2021 was included in this analysis. International Childhood Cancer Classification System was used for the classification. Essential demographic findings, ICD-O-3 morphology and topography codes were recorded for each case. Results: During the 13 years from 2009 to 2021, 24080 cases were registered. For all cases, median age was 6.7 year (0-19; M/F 13461/10609, 4 hermaphrodite, 6 unknown). Age distribution was 0-4 yrs, 40.8%; 5-9 yrs, 23.8%; 10-14 yrs, 23.3%; 15-19 yrs, 12.1%) The distribution of the tumor types were [number of cases, percentage of total, median age yrs, M/F]: Leukemia (5819, 24.2%, 5.5, 3366/2453); Lymphoma &amp; other RES tumors (4446, 18.5%, 9.8, 2956/1487, 1 hermaphrodite &amp; 2 unknown); CNS [brain &amp; spinal] (3730, 15.5%, 6.8, 2061/1668, 1 unkown); Symphatetic system (1965, 8.2%, 2.3, 1010/955); Retinoblastoma (675, 2.8%, 1.4, 375/300); Renal (1160, 4.8%, 3.1, 557/601, 1 hermaphrodite &amp; 1 unknown); Liver (409, 1.7%, 2.2, 234/175); Malignant bone (1584, 6.6%, 12.6, 864/720); Soft tissue sarcomas (1726, 7.2%, 7.7, 983/743); Germ cell (1593, 6.6%, 9.6, 588/1001, 2 hermaphrodite, 2 unknown); Carcinoma &amp; other malignant epithelial (804, 3.3%, 13.5, 381/423); Other/non-specific malignant (169, 0.7%, 7.9, 86/83). Five year survival rate was found as 72.3%. Conclusions: The registry shows that the survival rates for children and adolescents have been improved to 72% which reflects the status of the pediatric cancer care in Turkey. The data from this work became a valuable source for all stakeholders in national and international level working on improvement the pediatric cancer control.